Throughout this application various publications are referred to in parentheses. Full citations for these references may be found at the end of the specification before the claims. The disclosures of these publications are hereby incorporated by reference in their entireties into the subject application to more fully describe the art to which the subject application pertains.
The CSF-1R kinase (1,2) plays a critical role in the regulation of macrophage and osteoclast production and function (3-6) as well as the development and regulation of other cell types (7-11). The existence of an additional CSF-1R ligand was proposed based on the greater severity of phenotype of homozygous null CSF-1R mice, compared to the phenotype of homozygous CSF-1-null mutant mice (12). A second ligand for the CSF-1R, interleukin-34 (IL-34), with no apparent sequence similarity to any other growth factor, was subsequently identified (13). While IL-34 and CSF-1 compete for binding to the CSF-1R and have similar CSF-1R-mediated effects, they exhibit significant tissue specific and developmental differences in their expression patterns (14). In addition, whereas CSF-1-deficient mice exhibit partial loss of microglia, CSF-1R-deficient mice have no microglia (15). This observation, together with the high expression of IL-34 in brain suggested an important role of IL-34 in microglial development. In agreement with this, IL-34-deficient (IL-34−/−) mice were shown to exhibit severe deficits in microglia (16,76). Despite the similarity of IL-34 and CSF-1 in their CSF-1R-mediated effects (14,17), IL34 mRNA is expressed at a significantly higher level than either Csf1 or Csf1r mRNA in several regions of the early postnatal and adult brain (14) and IL-34 protein is often expressed in regions where there is minimal expression of the CSF-1R or CSF-1-reporter proteins and IL-34 is significantly more active in suppressing neural progenitor cell proliferation and neuronal differentiation than CSF-1 (9).
Protein tyrosine phosphatase receptor type zeta (PTP-ζ) (18,19), a cell-surface receptor and a chondroitin sulfate (CS) proteoglycan (CSPG), is highly abundant in the brain (20), primarily expressed on neural progenitors and glial cells (21-23) and binds to and signals through the action of multiple ligands (24) including the growth factor, pleiotrophin (PTN) (25,26), the cell-surface protein, contactin (CNTN) (27) and the extracellular matrix (ECM) protein, tenascin-R (TN-R) (28). The binding of some of these ligands involves the CS glycosaminoglycan (GAG)-moiety of PTP-ζ (25,29). Ligand binding to PTP-ζ leads to increased tyrosine phosphorylation of down-stream targets, including β-catenin, β-adducin, Src-family kinases (SFK), focal adhesion kinase (FAK), paxillin and extracellular signal-regulated kinase-1/2 (Erk-1/2) (30-37). PTP-ζ is up-regulated in many human cancers, including glioblastomas, and regulates their proliferation and migration (38-40).
The present invention addresses the need for activators and inhibitors of actions of IL-34 that are independent of the CSF-1R receptor and play a role in development, homeostasis and disease.